Is COMT p.Leu203= (c.609C>T) pathogenic?

COMT p.Leu203= (c.609C>T) is classified Benign in COMT (ClinVar, Single submitter, 1 submitter; last evaluated 2026-06-01). Common (popmax 6.29%, mid) — too common for a highly-penetrant pathogenic allele.

COMT p.Leu203=

Q: How common is COMT p.Leu203= (c.609C>T) in the general population?

COMT p.Leu203= (c.609C>T) is common (popmax 6.29%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.609C>T · rs165631 · VCV2652872

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 6.29%, mid) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.193	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.71	GERP -0.72, phastCons 0.001
Overall
CADD	2.475	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.29% Middle Eastern · 381/6,062 alleles

Filtering AF 5.76% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.56%

Overall 1.26% 20,271/1,613,988 alleles · common exomes 18,781/1,461,606 · genomes 1,490/152,382 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	6.29%	16
Ashkenazi Jewishnot grpmax-eligible	2.38%	42
South Asian	1.59%	63
Remaining individualsnot grpmax-eligible	1.48%	68
European (non-Finnish)	1.34%	75
Admixed American	1.03%	97
African / African-American	0.284%	352
Finnishnot grpmax-eligible	0.271%	369
East Asian	0.00891%	11,223

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: COMT
Protein: p.Leu203=
Coding: c.609C>T
MANE Select: NM_000754
dbSNP: rs165631
Type: single nucleotide variant
Location: chr22:19964293 (GRCh38)
Gene constraint: LOEUF 1.128 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.07 · 12 PDB
Residue 203: an α-helix

Full COMT gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TXNRD2 p.Ala5Val Uncertain significance ★★ same type
TXNRD2 p.Ala7Gly Uncertain significance ★★ same type
TXNRD2 p.Ala7Val Uncertain significance ★★ same type
TXNRD2 p.Arg9Pro Uncertain significance ★★ same type
TXNRD2 p.Gly10Ala Uncertain significance ★★ same type
TXNRD2 p.Gly10Val Uncertain significance ★★ same type
TXNRD2 p.Leu8Val Uncertain significance ★★ same type
TXNRD2 p.Met1Thr Uncertain significance ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/comt-p-leu203 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown